Elsevier

Neuroscience Letters

Volume 591, 30 March 2015, Pages 160-165
Neuroscience Letters

Research article
Genetic associations of CLU rs9331888 polymorphism with Alzheimer’s disease: A meta-analysis

https://doi.org/10.1016/j.neulet.2015.02.040Get rights and content

Highlights

  • Association of CLU rs9331888 with AD was found in Caucasians by meta-analysis.

  • No association of CLU rs9331888 with AD was found in Asian population.

  • No association of CLU rs9331888 with AD was found in pooled populations.

  • Sensitivity analysis found one study caused the heterogeneity in Asian subgroup.

Abstract

Recent studies showed the Clusterin gene (CLU) is associated with Alzheimer’s disease (AD). However, studies investigating the association of CLU single-nucleotide polymorphism (SNP) rs9331888 with AD are controversial. We then performed a meta-analysis to assess the association between CLU SNP rs9331888 and AD. Computerized bibliographic searches of PUBMED and AlzGene database were conducted for the period up to July, 2014. The strength of the association between SNP rs9331888 and AD was estimated by odds ratios (ORs) and OR 95% confidence intervals (CIs). A total of 11 studies composed of 8766 AD cases and 11,366 controls were included in this study. Significant association of SNP rs9331888 with AD was found in Caucasian population among allelic model (C vs. G: OR = 1.12, 95%CI = 1.06–1.17, P < 0.001), additive model (CC vs. GG: OR = 1.25, 95%CI = 1.12–1.40, P < 0.001), recessive model (CC vs. CG + GG: OR = 1.20, 95%CI = 1.07–1.34, P = 0.001), and dominant model (CC + CG vs. GG: OR = 1.13, 95%CI = 1.06–1.21, P < 0.001). No significant association among these models was found in Asian and overall populations. Sensitivity analysis found that one study caused the distinct heterogeneity in Asian subgroup. Our analysis demonstrated that CLU SNP rs9331888 might be associated with an increased AD risk in Caucasian population, but not in Asian population.

Introduction

Alzheimer’s disease (AD), the most common type of dementia among elderly people, is a fatal neurodegenerative disorder characterized neuropathologically by the extracellular accumulation of amyloid-β (Aβ) plaques, and the intracellular accumulation of hyperphosphorylated tau protein in the form of neurofibrillary tangles. The epidemiological data showed that one in eight people aged ≥65 years and around half of people aged ≥85 years have been affected by AD. By 2050, there is expected to be one new case of AD every 33 s, or nearly a million new cases per year [1].

AD is a complex and multi-factorial neurodegenerative disease with no effective treatment or cure. However, its etiological mechanisms remain unclear. Genetic factors have been reported to play an important role in the AD occurrence based on a large number of genetic linkage analyses and association studies, as well as the Genome-Wide Association Studies (GWAS) [2], [3]. In addition to the ϵ4 allele of the apolipoprotein E (ApoE), which has been recognized as the important gene for AD; other genes, such as CLU, CR1, BIN1,PICALM, EPHA1, CD2AP, CD33 and ABCA7, have also been shown to be significantly associated with AD [4], [5], [6], [7], [8], [9], [10]. Lamber et al.’s [7] study reported that three CLU SNPs, rs11136000, rs2279590 and rs9331888 were within a linkage disequilibrium block. Two meta-analyses indicated that strong association was identified between SNPs rs11136000 and rs2279590 with AD [11], [12]. But the susceptibility of CLU rs9331888 to AD remains inconclusive, especially among different ethnic populations. Therefore, to derive a more precise estimation of the CLU gene with AD, we performed a meta-analysis of case-control studies on the association between rs9331888 and AD, aiming to explore the role of this SNP in AD and to explain the possible reasons for inconsistency of the results among replicated studies.

Section snippets

Search strategy

To identify all relevant publications addressing the risk for AD associated with the CLU SNP rs9331888, we conducted a comprehensive literature search of electronic databases, including the PUBMED (updated on July 2014) and the AlzGene (http://alzgene.org, updated April18, 2011), limited to English language literature. The search strategy was based on the following search term/phase, “Alzheimer’s disease or AD” and “CLU or Clusterin or ApoJ or rs9331888” and “polymorphism or mutation or

Literature search and characteristics

A flow diagram showing the selection process of studies included in our analysis is shown in Fig. 1. The initial search strategy yielded 56 potential articles. After a careful abstract and/or full-text review, 49 studies were excluded for the following reasons: 5 were reviews and letters, 32 articles were unrelated topics addressing the association of other CLU SNPs but not rs9331888 with AD, two were the gene expression in the brain tissues of AD patients, six were not case-control design

Discussion

Clusterin (CLU), also known as apolipoprotein J (Apo J), is a glycoprotein which has been studied to play a pivotal role in the pathogenesis of AD [20], [21]. Several studies showed that significant association existed in the ApoE and CLU genes, and the clusterin levels were positively correlated with the number of ApoEϵ4 alleles [22], [23]. Therefore, the concerns on the CLU gene as AD risk factors have been raised [21], [24]. In Alzgene database, CLU SNP rs9331888 was not pooled for analysis

Conclusion

In summary, CLU SNP rs9331888 displayed significant association with AD in Caucasian population, not in Asians according to our results. For better understanding the role of the CLU gene and its mechanisms in AD pathogenesis, a more accurate classification of disease and subdivided groups based on disease progression or cognitive decline level may be critical on study designs. Hence well-designed and high quality studies with large sample size are required for in-depth investigation on the

Acknowledgements

This work was supported in part by grants from the Youth Doctoral Scientific Project of Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital (2014), the Health care for Cadres Project of Sichuan Provincial Health Department (2013206(P.S.) and the Natural Science Foundation of China (81371048 (B.G.)).

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    These authors contributed equally to this study.

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